Physicians have long recognised that conditions affecting the upper gastrointestinal (GI) tract commonly produce upper abdominal pain, discomfort, abdominal fullness, bloating, early satiety, nausea, vomiting, belching, heartburn and regurgitation. Such symptoms are typically postprandial and occur either alone or in combination. Overall, upper GI symptoms, including both dyspeptic-type and reflux-type, affect more than 25% of adults in the Western world and have a significant, negative impact on both functional status and sense of individual well-being (Tougas et al., Am J Gastroenterol. 1999; 94: 2845-2854). Symptoms related to disorders of upper gut function are among the most common presenting complaints in primary-care and GI specialty medical practice. These disorders commonly include, but are not limited to, GERD (gastroesophageal reflux disease), GERD with erosion, NERD (non-erosive reflux disease), NUD (non-ulcer dyspepsia), PUD (peptic ulcer disease), FD (functional dyspepsia), diabetic gastroparesis, gastrointestinal ulcers, Zollinger-Ellison syndrome, and antral G-cell hyperplasia.
Upper GI disorders are typically classified by anatomic region, e.g., those of esophageal origin and those of gastroduodenal origin, based on epidemiological evidence pointing to the existence of site-specific clusters of symptoms. However, the GI tract's anatomic continuity and integrated function in digestion and absorption of nutrients makes the separation of symptom clusters by site somewhat artificial. In fact, considering the diaphragm to be an anatomic boundary for defining upper GI disorders, e.g., attributing symptoms localised above the diaphragm such as heartburn to the esophagus, a thoracic organ, and symptoms localised below the diaphragm such as epigastric pain and discomfort to the stomach, an abdominal organ, has not been a very useful construct. For example, “heartburn” as the sole or predominant symptom to define gastroesophageal reflux disease (GERD) has very low sensitivity (38%) albeit high specificity (about 90%) (Dent et al., Gut. 2004, 53 (May): Supp 4:1-24). Rather than occurring alone as a manifestation of GERD, heartburn is associated with epigastric pain in at least two thirds of patients. Equally disturbing from the vantage point of defining upper GI disorders by location of symptoms, is the situation for dyspepsia. In a Danish study, 500 patients with dyspeptic symptoms (pain or discomfort in the epigastrium with or without heartburn, regurgitation, nausea, vomiting or bloating) were referred by their general practitioners for enrolment in a study comparing treatment strategies (H. pylori test—and eradicate versus prompt endoscopy) (Lassen et al, Lancet 2000, 356:455-460). Although the main entry criterion was epigastric pain or discomfort, which was reported by all patients, 32% had heartburn and/or regurgitation as their dominant symptom, which was almost as many patients as had dominant epigastric pain (37%). (See Lassen et al) Therefore, the available data indicate that significant overlap of symptoms exists in esophageal and gastric disorders; GERD patients have dyspeptic symptoms and dyspeptic patients have heartburn and/or regurgitation.
Given on the one hand the above described overlap of symptoms in patients with upper GI disorders and on the other hand the multiplicity of the underlying mechanisms of upper GI disorders, it is very unlikely that a pharmacological intervention directed versus a single chemical class represents an effective strategy for treating any upper GI disorders.
As the goal for the management of patients with upper GI disorders is aimed to provide symptom relief, improved quality of life and healing of any macroscopical lesion, if present, dyspeptic symptoms associated with upper GI disorders, therefore, represent an area of unmet need because there is no approved treatment for dyspeptic symptoms in patients. In addition, while there is compelling evidence for the effectiveness of acid suppression therapy in patients with symptomatic heartburn and/or regurgitation due to GERD, there is lack of convincing evidence of effectiveness of acid suppression therapy for dyspeptic symptoms associated with GERD. Indeed, it is a frequent observation that the majority of patients treated with a PPI for GERD symptoms are left with residual dyspeptic symptoms and treatment with standard PPI therapy for dyspeptic symptoms rarely show more than 10% efficacy advantage of PPI over placebo.
In addition, there are still some areas that can be identified where treatment of patients with GERD could be further refined or enhanced (Vakil N. Aliment Pharmacol Ther 2004; 19: 1041-1049), which include: lack of complete symptom control, as 75% of patients continued to experience heartburn frequently (Crawley J A, Schmitt C M. J Clin Outcomes Management 2000; 7: 29-34); variability in the inhibition of gastric acid secretion (Chiverton S G. Aliment Pharmacol Ther 1992; 6: 103-111); effective 24-h control of intragastric pH (Hatelbakk J G et al. Aliment Pharmacol Ther 1998; 12: 1235-1240; Katz P O et al. Aliment Pharmacol Ther 2000; 14: 709-714); onset of action, as all currently available PPS may take 3-5 days to achieve maximal acid inhibition at therapeutic doses (Tytgat G N. Eur J Gastroenterol Hepatol 2001; 13 (Suppl. 1): S29-33).
In particular, the slow onset of action is an intrinsic limitation of all exiting PPIs used a monotherapy in GERD as it is strictly linked to the pharmacokinetics and mode of action of all PPIs. After absorption and distribution PPIs given their pKa accumulate in the acid space of the canaliculus of secreting parietal cell where they are transformed into the active sulphenamide which forms non-competitive, covalent and irreversible bonds with the key cysteines of the H+, K+-APTase (Sachs G et al. Annu Rev Pharmacol Toxicol 1995; 35: 277-305). Due to the irreversible nature of this binding, a steady-state inhibition is achieved only after 3 or 4 days of treatment. This can be attributed to their very short half-life in combination with an activation of over 75% of the pumps and constant pump turnover in the face of covalent inhibition of the pump (Sachs G. Eur J Gastroenterol Hepatol. 2001; 13 (Suppl. 1): S35-S41).
Different strategies might be used to overcome the slow onset of action of all existing PPIs and possibly the scarce effect on dyspeptic symptoms.
For example new drugs are being developed such as the new class of Potassium-competitive acid blockers (P-CABs) which might offer a faster onset of action as these drugs bind ionically to the proton pump at or near the potassium-binding site in a K+-competitive manner, thereby blocking acid secretion through a direct, reversible mechanism (Pope A J, Sachs G. Best Pract Res Clin Gastroenterol 2002; 16: 835-849; Wurts W, Hartmann M. Yale J Biol Med 1996; 69: 233-243).
An alternative approach might be represented by the combination of a PPIs to an anti-secretive drug acting with a different mechanism of action for example at receptors involved in the regulation of gastric acid secretion, like H2 or CCK-2 (formerly “gastrin”) receptor antagonist. These antagonists although not as efficacious as PPIs in inhibiting gastric acid secretion, act faster than PPIs as they are reversible antagonists, and therefore might be used in combination with PPIs to reach the goal of quickly achieving and then maintaining adequate inhibition of gastric acid secretion, thus with a faster and more complete symptom relief.
Of particular interest is the combination of PPIs with CCK-2 receptor antagonists which might offer a unique advantage among all anti-secretive drugs as, due to their mode of action, in addition to the antisecretive properties, they are also able to counteract the unavoidable consequences of the hypergastrinemia which inevitably accompanies the reduction of intragastric acid secretion, regardless of the means used to achieve it, as the reduced acidity inevitably leads to the increased release of gastrin by antral G cells (Maton P N. N Engl J Med 1991; 324: 965-975). In addition, CCK 2 receptor antagonists might be able to block other effects of cholecystokinin (CCK) and/or gastrin (see below).
CCK belongs to the group of substances known as brain-gut peptides and function as a neuropeptide and as a gut hormone. (Noble et al., Pharmacol. Rev. 1999, 51(4):745-781; Crawley et al., Peptides 1994, 15(4):731-755). It is now evident that at least two different receptors, namely CCK-1 (formerly CCKA or alimentary) and CCK-2 (formerly CCKB or brain) receptors, mediate CCK biological actions. (Noble et al., Pharmacol. Rev., 1999, 51(4):745-781; Woodruff and Hughes, Ann. Rev. Pharmacol. 1991, 31:469-501).
CCK is secreted primarily in response to meals and plays a well-recognised role in regulating gallbladder contraction and pancreatic enzyme secretion. Over the last decade, considerable evidence has emerged to support the concept that CCK plays an equally important role in the regulation of motor and sensory functions at various levels of the human upper GI tract. Specifically, the native peptide delays gastric emptying, modulates gastric sensory function (especially in response to fat), increases the rate of meal-induced, transient lower esophageal sphincter relaxations (TLESRs) and affects small bowel and colonic transit.
Gastrin is closely related to CCK and is secreted by G cells located in the gastric antral mucosa and upper small intestine. Gastrin exerts three main gastrointestinal effects: stimulation of acid secretion directly from parietal cells; stimulation of acid production via increased histamine release from enterochromaffin like (ECL) cells and stimulation of somatostatin release (Schubert et al., Yale J. Biol. Med 1992; 65: 553-60). Furthermore, gastrin has a trophic effect on the gastric mucosa and stimulates the growth of gastrin-sensitive malignant cells (Rehfeld et al., Adv. Cancer Res. 1994, 63: 295-347).
CCK/gastrin receptors have been classified based on their anatomical location. The CCK1-subtype has been found in the gallbladder, pancreas and intestine. The CCK2-subtype has been found in discrete regions of the brain such as the cerebral cortex, hippocampus, nucleus accumbens, caudate-putamen and thalamus. Extensive evidence now indicates that CCK1 receptors are also present in the brain and conversely that CCK2 receptors are also present in the periphery, principally in the stomach. Furthermore, both receptors are expressed on human lower esophageal sphincter (LOS) (Gonzales et al., Neurogastroenterol. Mot. 2000; 12, 539-546).
Gastrin is released in response to food or in response to the neutralisation of stomach pH (Walsh, Gastrointestinal Hormones in Physiology of the Gastrointestinal Tract. Johnos L. R. (Ed.), Raven Press: New York. 1987, 181-259). The increase of circulating gastrin plasma levels stimulates the proliferation of the oxyntic mucosal cells, in particular the parietal and ECL cells (Enochs et al., Am. J. Physiol. 1977, 223: E223).
Elevated fasted and postprandial gastrin levels have been described in several diseases such as peptic ulcer, Zoelliger-Ellison syndrome, gastrinomas, and G-cells hyperplasia (Modlin et al, Gastroenterology 1996, 111:783-810). Moreover chronic infection with Helicobacter pylori is associated with increased basal and gastrin stimulated gastric acid secretion (McGowan et al., Gastroenterology 1996, 110: 926-938).
Therefore, CCK2 receptor antagonists may have a therapeutic potentials as antisecretory drugs, in peptic ulcer disease as well as in all those pathological conditions characterised by an hypertrophy of the gastric mucosa.
Itriglumide (Code Number CR 2945), (R)-1-napthalenepropanoic acid-β[2[(2-(8-azaspiro[4.5.]dec-8-ylcarbonyl)4,6-dimethyl-phenyl]amino]-2-oxoethyl] is a novel, non peptide CCK2 receptor antagonist developed by Rottapharm, formerly Rotta Research Laboratorium. The pharmacological profile of the compound is characterised by a high potency, selectivity and favourable toxicological profile (Makovec et al., Eur. J. Pharmacol., 1999, 369: 81-90).
Yet, the combination of a PPI and Itriglumide has not been described for a treatment of gastrointestinal disorders, even if some pharmaceutical compositions comprising CCK-B antagonists and a proton pump inhibitors to control gastric acid secretion in gastrointestinal disorders have been described in the literature. (See WO04/098610, WO04/101533, WO04/098609, WO03/041714, WO01/90078, WO01/85724, WO01/85723, WO01/85704, WO01/85167, and WO93/12817).